The present invention relates to novel phosphorus containing compounds useful as pharmaceutical agents, to methods for their production, to pharmaceutical compositions which include these compounds, and a pharmaceutically acceptable carrier, and to pharmaceutical methods of treatment. More particularly, the novel compounds of the present invention prevent the intestinal absorption of cholesterol in mammals by inhibiting the enzyme acyl-coenzyme A (Acyl-CoA):cholesterol acyltransferase (ACAT).
The atheromatous plaque, which is the characteristic lesion of atherosclerosis, results from deposition of plasma lipids, mainly cholesteryl esters, in the intima of the arterial wall. Progressive enlargement of the plaque leads to arterial constriction and ultimately coronary heart disease. A number of clinical trials have shown a causal relationship between hypercholesterolemia and coronary heart disease.
Agents that control dietary cholesterol absorption moderate serum cholesterol levels. Dietary cholesterol is absorbed from the intestinal lumen as free cholesterol which must be esterified with fatty acids. This reaction is catalyzed by the enzyme acyl-CoA:cholesterol acyltransferase (ACAT). The resulting cholesteryl esters are packaged into the chylomicrons which are secreted into the lymph. Inhibitors of ACAT not only prevent absorption of dietary cholesterol but also prevent the reabsorption of cholesterol which has been released into the intestine through endogenous regulatory mechanisms, thus lowering serum cholesterol levels and ultimately counteracting the formatting or development of atherosclerosis.
Compounds of the formula ##STR1## wherein R is selected from the group consisting of hydrogen, C.sub.1 -C.sub.4 alkyl, phenyl, and phenyl substituted with X; X represents one or more substituents independently selected from the group consisting of hydrogen, C.sub.1 -C.sub.4 alkyl, hydroxy, C.sub.1 -C.sub.4 alkoxy, halo, and nitro; Y represents one or more substituents independently selected from the group consisting of hydrogen, C.sub.1 -C.sub.4 alkyl, hydroxy, C.sub.1 -C.sub.4 alkoxy, halo, trifluoromethyl, nitro, amino, acetamido, acetyl, formyl, cyano, carboxy, C.sub.1 -C.sub.4 carboalkoxy, carboxamido, sulfonamido, --CO.sub.2 CH.sub.2 CO.sub.2 C.sub.2 H.sub.5, --CO.sub.2 CH.sub.2 CO.sub.2 CH.sub.3, and --CO.sub.2 CH.sub.2 CO.sub.2 H; and Q is selected from the group consisting of C.sub.1 -C.sub.4 alkyl and phenyl are disclosed as intermediates to prepare a series of substituted aralkanamidobenzoic acids in U.S. Pat. No. 4,536,346.
A method of controlling undesirable plant growth with a compound of the general formula ##STR2## wherein Z.sub.1, Z.sub.2, and Z.sub.3 are independently selected from the group consisting of sulfur and oxygen; R.sub.1 is aryl; R.sub.2 is selected from the group consisting of alkyl, aralkyl and aryl; R.sub.3 and R.sub.4 are independently selected from the group consisting of alkyl, hydroxyalkyl, unsubstituted aryl, substituted aryl, alkenyl, aralkyl, and hydrogen; provided a maximum of one of R.sub.3 and R.sub.4 is hydrogen. It is preferred that R.sub.1 be selected from the group consisting of unsubstituted aryl containing six to ten carbon atoms and substituted aryl wherein the substituents are selected from the group consisting of alkyl containing one to ten carbon atoms, halogen and mixtures thereof; R.sub.2 be independently selected from the group consisting of alkyl containing one to ten carbon atoms, aralkyl containing seven to twenty carbon atoms, and aryl containing six to twenty carbon atoms; R.sub.3 and R.sub.4 be independently selected from the group consisting of alkyl containing one to ten carbon atoms, hydroxyalkyl containing one to ten carbon atoms, unsubstituted aryl containing six to ten carbon atoms, substituted aryl wherein the substituents are selected from the group consisting of alkyl containing one to ten carbon atoms, halogen and mixtures thereof, alkenyl containing two to ten carbon atoms, aralkyl containing seven to twenty carbon atoms and hydrogen, provided a maximum of one of R.sub.3 and R.sub.4 is hydrogen is disclosed in U.S. Pat. No. 3,385,689.
A process for controlling undesirable plant life with the use of chemical compounds of the general formula ##STR3## wherein Z.sub.1, Z.sub.2, and Z.sub.3 are independently selected from the group consisting of sulfur and oxygen; R.sub.1 is aryl; R.sub.2 is selected from the group consisting of alkyl, aralkyl and aryl; R.sub.3 and R.sub.4 are independently selected from the group consisting of alkyl, alkylene, acyl, aryl, aralkyl, hydroxyalkyl, alkenyl, cycloalkyl, and hydrogen provided that a maximum of one of R.sub.3 and R.sub.4 is hydrogen; n is an integer of from 0 to 1; and X is selected from the group consisting of oxygen, sulfur, &gt;NY and &gt;CHY wherein Y is selected from the group consisting of lower alkyl and hydrogen, provided that when n is 0, R.sub.3 and R.sub.4 are selected from the group consisting of alkyl, acyl, aryl, aralkyl, hydroxyalkyl, alkenyl, cycloalkyl, and hydrogen provided that a maximum of one of R.sub.3 and R.sub.4 is hydrogen and when n is 1, R.sub.3 and R.sub.4 are alkylene is disclosed in U.S. Pat. No. 3,449,109.
A series of compounds of the formula ##STR4## wherein R is independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, alkenyl, aryl, aralkyl, and cycloalkyl groups and hydrogen; R' is independently selected from the group consisting of alkyl, hydroxyalkyl, aryl, alkenyl, aralkyl, and cycloalkyl groups and hydrogen, provided that a maximum of one of R and R, is hydrogen; Z, Z', and Z" are independently selected from the group consisting of oxygen and sulfur; and R" and R"' are independently selected from the group consisting of alkyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, aryl, aryloxy, arylthio, aralkyl, aralkoxy, and aralkylthio groups, provided that when one or both of R and R' are selected from the group consisting of hydroxyalkyl, alkenyl, aryl, aralkyl, and cycloalkyl groups and hydrogen, or R is alkyl, R" is selected from the group consisting of alkoxy, aralkoxy, and aryloxy, and R"' is aryloxy useful for the control of undesirable plant life is disclosed in Canadian Patent 780,800.
A series of compounds of the formula ##STR5## in which each of R.sub.1, R.sub.2, and R.sub.3 are hydrogen, halogen, preferably chlorine, alkyl, preferably of one to four carbon atoms, or nitro, R.sub.4 is lower alkyl, preferably with one to four carbon atoms, X is oxygen or sulfur and each of A and B is alkyl amino such as mono- and dialkyl amino or alkoxy, preferably those where the alkyl is of one to four carbon atoms useful as plant growth regulating compounds is disclosed in U.S. Pat. No. 3,384,683.
However, the compounds described in the aforementioned references do not disclose or suggest the combination of structural variations nor the use in preventing the intestinal absorption of cholesterol of the compounds of the present invention described hereinafter.